This invention relates to a method of conducting hormone replacement therapy (HRT) and to dispensers and kits adapted to practice the method.
HRT in women during the menopausal and post-menopausal period of their lives to prevent or at least diminish the adverse physiological effects thereof, such as bone loss and resultant structural deformation, is now conventional therapy, irrespective of whether the menopause is surgically induced or is the result of the normal aging process. HRT usually involves either the concurrent administration of both an estrogen and a progestogen on a constant, e.g., daily, basis or constant administration of an estrogen and intermittent, e.g., on the 10th to 14th days of a 28 day cycle, administration of the progestogen, at respective dosages which often are changed during the period of HRT, depending on the symptoms currently being displayed by an individual as a result of the menopausal state, the HRT or both. Those doses may be changed infrequently, e.g., every six months or longer at the time the individual visits her doctor for a routine examination, or more often, e.g., from month to month or even more frequently, if the individual is experiencing undesirable menstrual symptoms, e.g., irregular menses, break through bleeding, which is a common consequence of an imbalace of estrogens and progestogens in a continuous combined HRT regimin, excessive blood flow, severe bleeding pain or cramps or a number of other symptoms consistent with the dosage of one or both of the estrogen and the progestogen being too high and thereby creating hormonal side effects, e.g., breast tenderness, nausea, edema, menstrual disorders, etc., or too low and thereby limiting the efficacy of the HRT or creating other side effects. Moreover, because menopause involves a gradual reduction in circulating serum estrogen and progestogen levels, it is usually desirable to initiate HRT during the peri-menopausal period at lower dosages of the estrogen and/or progestogen and gradually increase the dosage thereof as menopause progresses. In addition, a full replacement dosage of estrogens may not be tolerable in a postmenopausal woman whose body has been adapting to estrogen deficiency over a certain period and who may experience breast tension, nausea, oedema and other typical side-effects when receiving the full dosage. In these women, one may wish to start with a very small dosage and increase it only gradually until symptoms have disappeared or plasma levels have reached premenopausal values. Modifying the progesterone dosage level also is frequently necessary during menopause to deal with menses irregularities.
Thus, a fixed combination of an estrogen dosage and a progestogen dosage that is suitable for all menopausal women is impossible to design, for a variety of reasons. One reason is the wide variation from individual to individual in the resorption rate which exists with all modes of administration except intraveneous, which is not practiced in HRT. These differences in bioavailability can reach 100% or more. For example, the bioavailability of estradiol orally averages 5% of the oral dose, which means that in an individual it an be as low as 3% or as high as 6%. Another reason why a fixed combination is not suitable is because of variations in body weight and fat mass proportion, which has an endrocrine function because it contains enzymes to transform hormonal precursors into estrogens. A third reason is the interaction between estrogens and progestogens, i.e., progestogens may only become effective in the presence of estrogens because they stimulate the production of progestogen recepton.
Consequently, estrogens and progestogen which are formulated commercially for HRT typically are sold as combined estrogen/progestogen tablets in more than one dosage strengths. However, the physician is still limited as to the size of the single dose of the estrogen and the progesterone which can be prescribed by those commercially available. Moreover, providing an estrogen/progestogen combination in tablets of multiple strengths adds to the manufacturing cost of producing a combination of a specific estrogen and a specific progestogen and increases significantly the inventory required of pharmacies to make any commercially available combination available to thepatients to whom it is prescribed. Therefore, some pharmacies do not stock their estrogen/progestogen products in tablet form in all of the dosage strengths which are commercially available, which can limit the flexibility desired by physicians in a dosage protocol for an individual patient, which ideally is customized in accordance with the symptoms of that patient which are currently manifested by is her.
For the foregoing reasons, there is a need in HRT for a method of administering successive doses of a specific estrogen and a specific progestogen whereby the dosage of either or both can readily be changed by the attending physician or even, if desired by the physician, by the patient, without the necessity of either the patient physically altering the physical form of that daily dosage, e.g., by cutting a tablet into segments, or the doctor prescribing a different form thereof, e.g., tablets of one or both of the hormones in higher or lower strengths. There is also a need for an HRT method which does not require the manufacturer to produce a plurality of products of different strengths in order to practice the method.
There is a further need for a method of self-administering the hormones during HRT by which the individual doses of the estrogen and the progestogen can easily and inexpensively and accurately be altered separately or simultaneously at various times during long term HRT without changing the prescribed dosage form for that patient.
There also is a need for a dispenser of the hormones which are prescribed and a kit comprising the dispenser for the HRT which permit the strength of the individual doses of the estrogen, of the progestogen or of both to be altered as frequently as and to the precise degree which the attending physician deems desirable.
The method of this invention meets these needs by employing in HRT a specific estrogen and a specific progestogen contained in separate extrudable pharmaceutical compositions and administering the compositions concurrently, i.e., either simultaneously as a mixture or in succession as separate extrudates.
The dispensers and kits of this invention meet these needs by dispensing the extrudable pharmaceutical compositions in metered or measured extruded segments.
There are a number of prior patents which disclose devices for dispensing a plurality of flowable materials, i.e., an extrudable solid or a viscous liquid. For a review of that art, see U.S. Pat. No. 5,020,694 and the references cited therein. See also U.S. Pat. Nos. 4,334,787, 4,687,663, 4,826,048, 4,838,457, 5,152,432, 5,240,146 and 5,339,990. Some of these, e.g., U.S. Pat. Nos. 4,240,146, 4,838,457 and 4,826,048, disclose dispensers which comprise means for varying the ratio and/or the quantity of the respective flowable materials which are dispensed in a single dispensing manipulator of the device. In U.S. Pat. No. 5,240,146, both the dosage of two separate injectable pharmaceutical compositions and the ratio thereof can be varied.
None of the prior art devices are directed specifically to the HRT method of this invention which involves, inter alia, one or more of transdermal administration, dosage and estrogen/progestogen ratio regulation and control; administration of the estrogen and the progestogen as extrudable semi-solids; a device or kit for administration of the estrogen and the progestogen which is simple and preferably contains a safeguard against the wrong dose of estrogen or progestogen or ratio thereof inadvertently being self-administered.
An object of the invention is to provide an HRT method of administering a combination of an estrogen and a progestogen in which the dosage of the estrogen or of the progestogen or of both can readily be changed periodically without the necessity of changing the prescribed form of the pharmaceutical composition.
Another object is to provide such a method in which the size of the dosage of only the estrogen or of only the progestogen or of both is changed only by the attending physician.
A further object is to provide such a method in which the size of the dosage of the estrogen only or of the progestogen only or patient to whom the hormones are prescribed, pursuant to instructions from her attending physician.
A further object is to provide such a method which permits a gradual approach to finding the lowest effective HRT dosage.
A further object is to provide a dispenser whereby the initial individual dose of either the estrogen of the progestogen employed in the methods of this invention or of both can readily and reliably be adjusted to any desired level and that dose can be increased or decreased by necessity of the physician prescribing a different commercial form thereof.
A further object is to provide such a method which permits an individual adjustment of the dosages of the estrogen and progestogen and which assures at the same time a concomitant use of both, similar to a fixed combination product. Thus, it provides the freedom of individual dosage and the reliability of compliance that can be achieved with a fixed combination.
A further object is to provide a dispenser whereby the initial individual dose of either the estrogen or of the progestogen employed in the methods of this invention or of both can readily and reliably be adjusted to any desired level and that dose can be increased or decreased by the attending physician or by the dispensing pharmacist by any amount desired by the physician without the necessity of the physician prescribing a different commercial form thereof.
Yet another object is to provide such a dispenser whereby such a change in the individual doses of either the estrogen or of the progestogen employed in the method of this invention or both can be readily and reliably be changed, either by the physician only or by the patient to whom the hormones are prescribed pursuant to instructions from her attending physician.
Still another object is to provide a kit by which one or more of the foregoing objects can be facilitated.
Other objects will be apparent to those skilled in the art to which this invention pertains.
In a method aspect, this invention relates to an HRT method of self-administration by a human female of successive doses of an estrogen and of a progestogen, wherein the female dispenses and self-administers successive individual doses of the estrogen and of the progestogen over a protracted period of time, during which period of time at least one of which doses is changed at least once, which method comprises the steps of:
a) dispensing to a delivery surface, from a first source of a first semisolid or viscous liquid pharmaceutically acceptable composition containing a plurality of non-discrete doses of the estrogen, a metered volume of the first composition as a single dose of the estrogen;
b) concurrently dispensing to the delivery surface, from a second source of a second semisolid or viscous liquid pharmaceutically acceptable composition containing a plurality of non-discrete doses of the progestogen, a metered volume of the second composition as a single dose of the progestogen;
c) transporting the metered volumes of the first and second compositions and the delivery surface concurrently to the site of administration of the estrogen and progestogen and administering the dispensed doses of estrogen and progestogen thereat;
d) repeating steps a)-c) on a predetermined schedule; and
e) periodically, in response to the physiological symptoms associated with menopause or the HRT currently exhibited by the female, changing the metered volume of at least one of the first and second compositions which are dispensed to the delivery surface as a single dose thereof.
In an article of manufacture aspect, this invention relates to a dispenser adapted for dispensing and self-administering a plurality of successive individual doses of an estrogen and a progestogen from a dispenser containing multiple doses of thereof in separate extrudable pharmaceutically acceptable compositions, in metered single dosage amounts which can simply and accurately be varied by mechanically modifying the dispenser, which comprises:
a) a first container comprising:
(i) a first chamber containing a plurality of doses of the estrogen in a first extrudable semi-solid or viscous liquid pharmaceutically acceptable composition;
(ii) a discharge port through which a volume of the first pharmaceutical composition in the first chamber can be discharged therefrom when discharging pressure is applied to the first container;
(iii) means for applying discharging pressure to the first chamber;
b) a second container comprising:
(i) a second chamber containing a plurality of doses of the progestogen in a second extrudable semi-solid or viscous liquid pharmaceutically acceptable composition;
(ii) a discharge port through which a volume of the second extrudable pharmaceutical composition in the second chamber can be discharged therefrom when discharging pressure is applied to the second container;
(iii) means for applying discharging pressure to the second chamber;
c) a first metering means adapted to receive a volume of the first extrudable pharmaceutical composition extruded thereinto from the first chamber and digitally reciprocally convertible from a receiving mode, where it communicates with the first chamber through the first port and can be filled with a predetermined volume of the first extrudable pharmaceutical composition, to a discharging mode, where a volume of the first extrudable pharmaceutical composition therein can be discharged therefrom and dispensed from the dispenser, which first metering means comprises:
(i) a first adjusting means for varying the volume of the first extrudable pharmaceutical composition which can be extruded into the first metering means a single dose of the estrogen;
d) a second metering means adapted to receive a volume of the second extrudable pharmaceutical composition extruded thereinto from the second chamber and digitally reciprocally convertible from a receiving mode, where it communicates with the second chamber through the second port and can be filled with a volume of the second extrudable pharmaceutical composition, to a discharging mode, where a volume of the second extrudable pharmaceutical composition therein can be discharged therefrom and dispensed from the dispenser, which second metering means comprises:
(i) a second adjusting means for varying the volume of the second extrudable pharmaceutical composition which can be extruded thereinto as a single dose of the progestogen; and
e) dispensing means for dispensing from the dispenser, as a single dose of the estrogen and the progestogen, a volume of the first pharmaceutical composition and a volume of the second pharmaceutical composition from the first and second metering means, respectively.